Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the TIMBAL database.

Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the TIMBAL database.

Chem Biol Drug Des. 2009 Nov;74(5):457-67

Authors: Higueruelo AP, Schreyer A, Bickerton GR, Pitt WR, Groom CR, Blundell TL

Growing evidence of the possibility of modulating protein-protein interactions with small molecules is opening the door to new approaches and concepts in drug discovery. In this paper, we describe the creation of TIMBAL, a hand-curated database holding an up to date collection of small molecules inhibiting multi-protein complexes. This database has been analysed and profiled in terms of molecular properties. Protein-protein modulators tend to be large lipophilic molecules with few hydrogen bond features. An analysis of TIMBAL's intersection with other structural databases, including CREDO (protein-small molecule from the PDB) and PICCOLO (protein-protein from the PDB) reveals that TIMBAL molecules tend to form mainly hydrophobic interactions with only a few hydrogen bonding contacts. With respect to potency, TIMBAL molecules are slightly less efficient than an average medicinal chemistry hit or lead. The database provides a resource that will allow further insights into the types of molecules favoured by protein interfaces and provide a background to continuing work in this area. Access at http://www-cryst.bioc.cam.ac.uk/timbal.

PMID: 19811506 [PubMed - in process]